The isolation or synthesis of new compounds potentially useful in the treatment of a variety of diseases has increased substantially over the years. Despite the availability of new compounds, their use is hampered by the fact that many are not water-soluble and thus require a carrier for transportation in aqueous environments. A carrier needs to be both safe and effective. The use of current carders is limited by toxicity problems (such as the induction of hypersensitivity reactions) and/or stability problems.
One example of a compound which, due to its unique solubility characteristics, must be formulated in a carrier is taxol. A diterpenoid derived from the bark of the Pacific Yew (Taxus brevifolia, Nutt), taxol is an exciting new anti-cancer drug with proven activity in the treatment of ovarian cancer. Despite the great interest in development of the drug for treatment of cancer, several significant obstacles have arisen concerning its use.
Taxol is formulated in cremophor EL, a common lipid emulsion used for hydrophobic drugs. Cremophor EL is polyoxyethylated castor oil in anhydrous ethanol (50:50). It is well established, however, that the solubilizing agent cremophor EL can promote acute toxic reactions typically expressed as hypersensitivity (Lassus et al., Proc. Am. Soc. Oncol. 4:268, 1985). At present, this is managed clinically though the use of premedication regimes with anti-inflammatory agents such as corticosteroids, antihistamines, dexamethasone and diphenhydramine. Even with premedication, 41% of all patients will exhibit a hypersensitivity reaction (Taxol package insert from Bristol-Myers Squibb; also, Kris et al., Cancer Treatment Reports 70(5):605, 1986). In order to reduce acute reactions to the present taxol formulation, the drug has to be given by intravenous infusion, typically over 24 hours. This step adds significantly to the cost of patient care.
An additional problem relates to the fact that the present formulation of taxol is very effective at extracting plasticizers, such as di-(2-ethylhexyl) phthalate from PVC infusion bags and tubing (Taxol package insert; and Waugh et al., American Journal of Hospital Pharmacists 48:1520, 1991). These plasticizers are known to promote toxic reactions, such as Adult Respiratory Distress Syndrome (ARDS), in patients which have been exposed to high levels. The present taxol formulation must be stored in glass or polypropylene bottles or bags and should be administered through polyethylenelined tubing. Thus the current formulation of taxol requires a lengthy infusion time and extra care in storage and administration, which adds substantially to the cost of the treatment. Taxol is an example of the need for a better formulation for hydrophobic compounds such as drugs.
Due to the difficulties in the current approaches to the delivery of hydrophobic compounds to the site of desired activity, there is a need in the art for improved compositions and methods. The present invention fulfills this need, and further provides other related advantages.